Molecular Neurobiology

, Volume 54, Issue 4, pp 3078–3101 | Cite as

Brain Iron Metabolism Dysfunction in Parkinson’s Disease

  • Hong JiangEmail author
  • Jun Wang
  • Jack Rogers
  • Junxia XieEmail author


Dysfunction of iron metabolism, which includes its uptake, storage, and release, plays a key role in neurodegenerative disorders, including Parkinson’s disease (PD), Alzheimer’s disease, and Huntington’s disease. Understanding how iron accumulates in the substantia nigra (SN) and why it specifically targets dopaminergic (DAergic) neurons is particularly warranted for PD, as this knowledge may provide new therapeutic avenues for a more targeted neurotherapeutic strategy for this disease. In this review, we begin with a brief introduction describing brain iron metabolism and its regulation. We then provide a detailed description of how iron accumulates specifically in the SN and why DAergic neurons are especially vulnerable to iron in PD. Furthermore, we focus on the possible mechanisms involved in iron-induced cell death of DAergic neurons in the SN. Finally, we present evidence in support that iron chelation represents a plausable therapeutic strategy for PD.


Parkinson’s disease Brain iron metabolism Iron transporters Iron regulatory protein Iron chelation 



We are deeply grateful to Prof. Yang XL, Fudan University, for his encouragement and critical comments on the manuscript. We thank Dr. Xu HM for revising the manuscript, and Dr. Song N and Dr. Ma ZG for their good suggestions to this paper. This work was supported by grants from the National Foundation of Natural Science of China (81430024, 31271131, 31471114, 31371081), from the National Program of Basic Research sponsored by the Ministry of Science and Technology of China (2011CB504100), from Ministry of Education of China (20123706110002) and from Excellent Innovative Team of Shandong Province and Taishan Scholars Construction Project.

Compliance with Ethical Standards

Competing Interests

The authors declare that they have no competing interests.


  1. 1.
    Schweitzer KJ, Brussel T, Leitner P, Kruger R, Bauer P, Woitalla D, Tomiuk J, Gasser T, Berg D (2007) Transcranial ultrasound in different monogenetic subtypes of Parkinson’s disease. J Neurol 254(5):613–616. doi: 10.1007/s00415-006-0369-7 PubMedCrossRefGoogle Scholar
  2. 2.
    Hagenah JM, Konig IR, Becker B, Hilker R, Kasten M, Hedrich K, Pramstaller PP, Klein C, Seidel G (2007) Substantia nigra hyperechogenicity correlates with clinical status and number of Parkin mutated alleles. J Neurol 254(10):1407–1413. doi: 10.1007/s00415-007-0567-y PubMedCrossRefGoogle Scholar
  3. 3.
    Hagenah JM, Becker B, Bruggemann N, Djarmati A, Lohmann K, Sprenger A, Klein C, Seidel G (2008) Transcranial sonography findings in a large family with homozygous and heterozygous PINK1 mutations. J Neurol Neurosurg Psychiatry 79(9):1071–1074. doi: 10.1136/jnnp.2007.142174 PubMedCrossRefGoogle Scholar
  4. 4.
    Bruggemann N, Hagenah J, Stanley K, Klein C, Wang C, Raymond D, Ozelius L, Bressman S, Saunders-Pullman R (2011) Substantia nigra hyperechogenicity with LRRK2 G2019S mutations. Mov Disord 26(5):885–888. doi: 10.1002/mds.23644 PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Xie W, Li X, Li C, Zhu W, Jankovic J, Le W (2010) Proteasome inhibition modeling nigral neuron degeneration in Parkinson’s disease. J Neurochem 115(1):188–199. doi: 10.1111/j.1471-4159.2010.06914.x PubMedCrossRefGoogle Scholar
  6. 6.
    Dexter DT, Wells FR, Lees AJ, Agid F, Agid Y, Jenner P, Marsden CD (1989) Increased nigral iron content and alterations in other metal ions occurring in brain in Parkinson’s disease. J Neurochem 52(6):1830–1836PubMedCrossRefGoogle Scholar
  7. 7.
    Bastian TW, Prohaska JR, Georgieff MK, Anderson GW (2010) Perinatal iron and copper deficiencies alter neonatal rat circulating and brain thyroid hormone concentrations. Endocrinology 151(8):4055–4065. doi: 10.1210/en.2010-0252 PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Ke Y, Ming Qian Z (2003) Iron misregulation in the brain: a primary cause of neurodegenerative disorders. Lancet Neurol 2(4):246–253PubMedCrossRefGoogle Scholar
  9. 9.
    Kaur D, Andersen J (2004) Does cellular iron dysregulation play a causative role in Parkinson’s disease? Ageing Res Rev 3(3):327–343. doi: 10.1016/j.arr.2004.01.003 PubMedCrossRefGoogle Scholar
  10. 10.
    Oakley AE, Collingwood JF, Dobson J, Love G, Perrott HR, Edwardson JA, Elstner M, Morris CM (2007) Individual dopaminergic neurons show raised iron levels in Parkinson disease. Neurology 68(21):1820–1825. doi: 10.1212/01.wnl.0000262033.01945.9a PubMedCrossRefGoogle Scholar
  11. 11.
    Jiang H, Song N, Xu H, Zhang S, Wang J, Xie J (2010) Up-regulation of divalent metal transporter 1 in 6-hydroxydopamine intoxication is IRE/IRP dependent. Cell Res. doi:  10.1038/cr.2010.20
  12. 12.
    Ward RJ, Zucca FA, Duyn JH, Crichton RR, Zecca L (2014) The role of iron in brain ageing and neurodegenerative disorders. Lancet Neurol 13(10):1045–1060. doi: 10.1016/S1474-4422(14)70117-6 PubMedCrossRefGoogle Scholar
  13. 13.
    Ayton S, Lei P (2014) Nigral iron elevation is an invariable feature of Parkinson’s disease and is a sufficient cause of neurodegeneration. Biomed Res Int 2014:581256. doi: 10.1155/2014/581256 PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Knutson M, Menzies S, Connor J, Wessling-Resnick M (2004) Developmental, regional, and cellular expression of SFT/UbcH5A and DMT1 mRNA in brain. J Neurosci Res 76(5):633–641. doi: 10.1002/jnr.20113 PubMedCrossRefGoogle Scholar
  15. 15.
    McCarthy RC, Kosman DJ (2012) Mechanistic analysis of iron accumulation by endothelial cells of the BBB. Biometals 25(4):665–675. doi: 10.1007/s10534-012-9538-6 PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Rouault TA, Zhang DL, Jeong SY (2009) Brain iron homeostasis, the choroid plexus, and localization of iron transport proteins. Metab Brain Dis. doi: 10.1007/s11011-009-9169-y
  17. 17.
    Aquino D, Bizzi A, Grisoli M, Garavaglia B, Bruzzone MG, Nardocci N, Savoiardo M, Chiapparini L (2009) Age-related iron deposition in the basal ganglia: quantitative analysis in healthy subjects. Radiology 252(1):165–172. doi: 10.1148/radiol.2522081399 PubMedCrossRefGoogle Scholar
  18. 18.
    Pfefferbaum A, Adalsteinsson E, Rohlfing T, Sullivan EV (2009) MRI estimates of brain iron concentration in normal aging: comparison of field-dependent (FDRI) and phase (SWI) methods. Neuroimage 47(2):493–500. doi: 10.1016/j.neuroimage.2009.05.006 PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Zecca L, Stroppolo A, Gatti A, Tampellini D, Toscani M, Gallorini M, Giaveri G, Arosio P, Santambrogio P, Fariello RG, Karatekin E, Kleinman MH, Turro N, Hornykiewicz O, Zucca FA (2004) The role of iron and copper molecules in the neuronal vulnerability of locus coeruleus and substantia nigra during aging. Proc Natl Acad Sci U S A 101(26):9843–9848. doi: 10.1073/pnas.0403495101 PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Carlson ES, Fretham SJ, Unger E, O’Connor M, Petryk A, Schallert T, Rao R, Tkac I, Georgieff MK (2010) Hippocampus specific iron deficiency alters competition and cooperation between developing memory systems. J Neurodev Disord 2(3):133–143. doi: 10.1007/s11689-010-9049-0 PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Carlson ES, Tkac I, Magid R, O’Connor MB, Andrews NC, Schallert T, Gunshin H, Georgieff MK, Petryk A (2009) Iron is essential for neuron development and memory function in mouse hippocampus. J Nutr 139(4):672–679. doi: 10.3945/jn.108.096354 PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Benton D (2010) The influence of dietary status on the cognitive performance of children. Mol Nutr Food Res 54(4):457–470. doi: 10.1002/mnfr.200900158 PubMedCrossRefGoogle Scholar
  23. 23.
    Millichap JG (2008) Etiologic classification of attention-deficit/hyperactivity disorder. Pediatrics 121(2):e358–e365. doi: 10.1542/peds.2007-1332 PubMedCrossRefGoogle Scholar
  24. 24.
    Trenkwalder C, Paulus W (2010) Restless legs syndrome: pathophysiology, clinical presentation and management. Nat Rev Neurol 6(6):337–346. doi: 10.1038/nrneurol.2010.55 PubMedCrossRefGoogle Scholar
  25. 25.
    Baumann N, Pham-Dinh D (2001) Biology of oligodendrocyte and myelin in the mammalian central nervous system. Physiol Rev 81(2):871–927PubMedGoogle Scholar
  26. 26.
    Benarroch EE (2009) Brain iron homeostasis and neurodegenerative disease. Neurology 72(16):1436–1440. doi: 10.1212/WNL.0b013e3181a26b30 PubMedCrossRefGoogle Scholar
  27. 27.
    Moos T, Morgan EH (2000) Transferrin and transferrin receptor function in brain barrier systems. Cell Mol Neurobiol 20(1):77–95PubMedCrossRefGoogle Scholar
  28. 28.
    Waheed A, Britton RS, Grubb JH, Sly WS, Fleming RE (2008) HFE association with transferrin receptor 2 increases cellular uptake of transferrin-bound iron. Arch Biochem Biophys 474(1):193–197. doi: 10.1016/ PubMedCrossRefGoogle Scholar
  29. 29.
    Kawabata H, Yang R, Hirama T, Vuong PT, Kawano S, Gombart AF, Koeffler HP (1999) Molecular cloning of transferrin receptor 2. A new member of the transferrin receptor-like family. J Biol Chem 274(30):20826–20832PubMedCrossRefGoogle Scholar
  30. 30.
    Trinder D, Baker E (2003) Transferrin receptor 2: a new molecule in iron metabolism. Int J Biochem Cell Biol 35(3):292–296PubMedCrossRefGoogle Scholar
  31. 31.
    Fleming RE (2009) Iron sensing as a partnership: HFE and transferrin receptor 2. Cell Metab 9(3):211–212. doi: 10.1016/j.cmet.2009.02.004 PubMedCrossRefGoogle Scholar
  32. 32.
    Ganz T (2008) Iron homeostasis: fitting the puzzle pieces together. Cell Metab 7(4):288–290. doi: 10.1016/j.cmet.2008.03.008 PubMedCrossRefGoogle Scholar
  33. 33.
    Kielmanowicz MG, Laham N, Coligan JE, Lemonnier F, Ehrlich R (2005) Mouse HFE inhibits Tf-uptake and iron accumulation but induces non-transferrin bound iron (NTBI)-uptake in transformed mouse fibroblasts. J Cell Physiol 202(1):105–114. doi: 10.1002/jcp.20095 PubMedCrossRefGoogle Scholar
  34. 34.
    Lee PL, Beutler E (2009) Regulation of hepcidin and iron-overload disease. Annu Rev Pathol 4:489–515. doi: 10.1146/annurev.pathol.4.110807.092205 PubMedCrossRefGoogle Scholar
  35. 35.
    Waheed A, Grubb JH, Zhou XY, Tomatsu S, Fleming RE, Costaldi ME, Britton RS, Bacon BR, Sly WS (2002) Regulation of transferrin-mediated iron uptake by HFE, the protein defective in hereditary hemochromatosis. Proc Natl Acad Sci U S A 99(5):3117–3122. doi: 10.1073/pnas.042701499 PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Lopez V, Suzuki YA, Lonnerdal B (2006) Ontogenic changes in lactoferrin receptor and DMT1 in mouse small intestine: implications for iron absorption during early life. Biochem Cell Biol 84(3):337–344. doi: 10.1139/o06-059 PubMedCrossRefGoogle Scholar
  37. 37.
    Mackenzie B, Takanaga H, Hubert N, Rolfs A, Hediger MA (2007) Functional properties of multiple isoforms of human divalent metal-ion transporter 1 (DMT1). Biochem J 403(1):59–69. doi: 10.1042/BJ20061290 PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Konofal E, Lecendreux M, Deron J, Marchand M, Cortese S, Zaim M, Mouren MC, Arnulf I (2008) Effects of iron supplementation on attention deficit hyperactivity disorder in children. Pediatr Neurol 38(1):20–26. doi: 10.1016/j.pediatrneurol.2007.08.014 PubMedCrossRefGoogle Scholar
  39. 39.
    Konofal E, Cortese S, Marchand M, Mouren MC, Arnulf I, Lecendreux M (2007) Impact of restless legs syndrome and iron deficiency on attention-deficit/hyperactivity disorder in children. Sleep Med 8(7-8):711–715. doi: 10.1016/j.sleep.2007.04.022 PubMedCrossRefGoogle Scholar
  40. 40.
    Sekyere EO, Dunn LL, Rahmanto YS, Richardson DR (2006) Role of melanotransferrin in iron metabolism: studies using targeted gene disruption in vivo. Blood 107(7):2599–2601. doi: 10.1182/blood-2005-10-4174 PubMedCrossRefGoogle Scholar
  41. 41.
    Ben-Shachar D, Eshel G, Finberg JP, Youdim MB (1991) The iron chelator desferrioxamine (Desferal) retards 6-hydroxydopamine-induced degeneration of nigrostriatal dopamine neurons. J Neurochem 56(4):1441–1444PubMedCrossRefGoogle Scholar
  42. 42.
    Lin AM, Ho LT (2000) Melatonin suppresses iron-induced neurodegeneration in rat brain. Free Radic Biol Med 28(6):904–911PubMedCrossRefGoogle Scholar
  43. 43.
    Patel BN, Dunn RJ, Jeong SY, Zhu Q, Julien JP, David S (2002) Ceruloplasmin regulates iron levels in the CNS and prevents free radical injury. J Neurosci 22(15):6578–6586, 20026652PubMedGoogle Scholar
  44. 44.
    Burdo JR, Menzies SL, Simpson IA, Garrick LM, Garrick MD, Dolan KG, Haile DJ, Beard JL, Connor JR (2001) Distribution of divalent metal transporter 1 and metal transport protein 1 in the normal and Belgrade rat. J Neurosci Res 66(6):1198–1207. doi: 10.1002/jnr.1256 PubMedCrossRefGoogle Scholar
  45. 45.
    Song N, Jiang H, Wang J, Xie JX (2007) Divalent metal transporter 1 up-regulation is involved in the 6-hydroxydopamine-induced ferrous iron influx. J Neurosci Res 85(14):3118–3126. doi: 10.1002/jnr.21430 PubMedCrossRefGoogle Scholar
  46. 46.
    Lee PL, Gelbart T, West C, Halloran C, Beutler E (1998) The human Nramp2 gene: characterization of the gene structure, alternative splicing, promoter region and polymorphisms. Blood Cells Mol Dis 24(2):199–215. doi: 10.1006/bcmd.1998.0186 PubMedCrossRefGoogle Scholar
  47. 47.
    Hubert N, Hentze MW (2002) Previously uncharacterized isoforms of divalent metal transporter (DMT)-1: implications for regulation and cellular function. Proc Natl Acad Sci U S A 99(19):12345–12350. doi: 10.1073/pnas.192423399 PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Howitt J, Putz U, Lackovic J, Doan A, Dorstyn L, Cheng H, Yang B, Chan-Ling T, Silke J, Kumar S, Tan SS (2009) Divalent metal transporter 1 (DMT1) regulation by Ndfip1 prevents metal toxicity in human neurons. Proc Natl Acad Sci U S A 106(36):15489–15494. doi: 10.1073/pnas.0904880106 PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Roth JA, Singleton S, Feng J, Garrick M, Paradkar PN (2010) Parkin regulates metal transport via proteasomal degradation of the 1B isoforms of divalent metal transporter 1 (DMT1). J Neurochem. doi:  10.1111/j.1471-4159.2010.06607.x
  50. 50.
    Ke Y, Chang YZ, Duan XL, Du JR, Zhu L, Wang K, Yang XD, Ho KP, Qian ZM (2005) Age-dependent and iron-independent expression of two mRNA isoforms of divalent metal transporter 1 in rat brain. Neurobiol Aging 26(5):739–748. doi: 10.1016/j.neurobiolaging.2004.06.002 PubMedCrossRefGoogle Scholar
  51. 51.
    Burdo JR, Martin J, Menzies SL, Dolan KG, Romano MA, Fletcher RJ, Garrick MD, Garrick LM, Connor JR (1999) Cellular distribution of iron in the brain of the Belgrade rat. Neuroscience 93(3):1189–1196PubMedCrossRefGoogle Scholar
  52. 52.
    Hulet SW, Hess EJ, Debinski W, Arosio P, Bruce K, Powers S, Connor JR (1999) Characterization and distribution of ferritin binding sites in the adult mouse brain. J Neurochem 72(2):868–874PubMedCrossRefGoogle Scholar
  53. 53.
    Chen TT, Li L, Chung DH, Allen CD, Torti SV, Torti FM, Cyster JG, Chen CY, Brodsky FM, Niemi EC, Nakamura MC, Seaman WE, Daws MR (2005) TIM-2 is expressed on B cells and in liver and kidney and is a receptor for H-ferritin endocytosis. J Exp Med 202(7):955–965. doi: 10.1084/jem.20042433 PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Todorich B, Zhang X, Slagle-Webb B, Seaman WE, Connor JR (2008) Tim-2 is the receptor for H-ferritin on oligodendrocytes. J Neurochem 107(6):1495–1505. doi: 10.1111/j.1471-4159.2008.05678.x PubMedCrossRefGoogle Scholar
  55. 55.
    Fisher J, Devraj K, Ingram J, Slagle-Webb B, Madhankumar AB, Liu X, Klinger M, Simpson IA, Connor JR (2007) Ferritin: a novel mechanism for delivery of iron to the brain and other organs. Am J Physiol Cell Physiol 293(2):C641–C649. doi: 10.1152/ajpcell.00599.2006 PubMedCrossRefGoogle Scholar
  56. 56.
    Li JY, Paragas N, Ned RM, Qiu A, Viltard M, Leete T, Drexler IR, Chen X, Sanna-Cherchi S, Mohammed F, Williams D, Lin CS, Schmidt-Ott KM, Andrews NC, Barasch J (2009) Scara5 is a ferritin receptor mediating non-transferrin iron delivery. Dev Cell 16(1):35–46. doi: 10.1016/j.devcel.2008.12.002 PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Ganz T (2005) Cellular iron: ferroportin is the only way out. Cell Metab 1(3):155–157. doi: 10.1016/j.cmet.2005.02.005 PubMedCrossRefGoogle Scholar
  58. 58.
    Kaplan J, Kushner JP (2000) Mining the genome for iron. Nature 403(6771):711–713. doi: 10.1038/35001691 PubMedCrossRefGoogle Scholar
  59. 59.
    McKie AT, Marciani P, Rolfs A, Brennan K, Wehr K, Barrow D, Miret S, Bomford A, Peters TJ, Farzaneh F, Hediger MA, Hentze MW, Simpson RJ (2000) A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation. Mol Cell 5(2):299–309PubMedCrossRefGoogle Scholar
  60. 60.
    Le NT, Richardson DR (2002) Ferroportin1: a new iron export molecule? Int J Biochem Cell Biol 34(2):103–108PubMedCrossRefGoogle Scholar
  61. 61.
    Jiang DH, Ke Y, Cheng YZ, Ho KP, Qian ZM (2002) Distribution of ferroportin1 protein in different regions of developing rat brain. Dev Neurosci 24(2-3):94–98PubMedCrossRefGoogle Scholar
  62. 62.
    Wu LJ, Leenders AG, Cooperman S, Meyron-Holtz E, Smith S, Land W, Tsai RY, Berger UV, Sheng ZH, Rouault TA (2004) Expression of the iron transporter ferroportin in synaptic vesicles and the blood-brain barrier. Brain Res 1001(1-2):108–117. doi: 10.1016/j.brainres.2003.10.066 PubMedCrossRefGoogle Scholar
  63. 63.
    Wang J, Jiang H, Xie JX (2007) Ferroportin1 and hephaestin are involved in the nigral iron accumulation of 6-OHDA-lesioned rats. Eur J Neurosci 25(9):2766–2772. doi: 10.1111/j.1460-9568.2007.05515.x PubMedCrossRefGoogle Scholar
  64. 64.
    Morita H, Ikeda S, Yamamoto K, Morita S, Yoshida K, Nomoto S, Kato M, Yanagisawa N (1995) Hereditary ceruloplasmin deficiency with hemosiderosis: a clinicopathological study of a Japanese family. Ann Neurol 37(5):646–656. doi: 10.1002/ana.410370515 PubMedCrossRefGoogle Scholar
  65. 65.
    Yoshida K, Furihata K, Takeda S, Nakamura A, Yamamoto K, Morita H, Hiyamuta S, Ikeda S, Shimizu N, Yanagisawa N (1995) A mutation in the ceruloplasmin gene is associated with systemic hemosiderosis in humans. Nat Genet 9(3):267–272. doi: 10.1038/ng0395-267 PubMedCrossRefGoogle Scholar
  66. 66.
    Wang J, Bi M, Xie J (2015) Ceruloplasmin is Involved in the Nigral Iron Accumulation of 6-OHDA-Lesioned Rats. Cell Mol Neurobiol 35(5):661–668. doi: 10.1007/s10571-015-0161-2 PubMedCrossRefGoogle Scholar
  67. 67.
    Boll MC, Sotelo J, Otero E, Alcaraz-Zubeldia M, Rios C (1999) Reduced ferroxidase activity in the cerebrospinal fluid from patients with Parkinson’s disease. Neurosci Lett 265(3):155–158PubMedCrossRefGoogle Scholar
  68. 68.
    Lei P, Ayton S, Finkelstein DI, Spoerri L, Ciccotosto GD, Wright DK, Wong BX, Adlard PA, Cherny RA, Lam LQ, Roberts BR, Volitakis I, Egan GF, McLean CA, Cappai R, Duce JA, Bush AI (2012) Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export. Nat Med 18(2):291–295. doi: 10.1038/nm.2613 PubMedCrossRefGoogle Scholar
  69. 69.
    Duce JA, Tsatsanis A, Cater MA, James SA, Robb E, Wikhe K, Leong SL, Perez K, Johanssen T, Greenough MA, Cho HH, Galatis D, Moir RD, Masters CL, McLean C, Tanzi RE, Cappai R, Barnham KJ, Ciccotosto GD, Rogers JT, Bush AI (2010) Iron-export ferroxidase activity of beta-amyloid precursor protein is inhibited by zinc in Alzheimer’s disease. Cell 142(6):857–867. doi: 10.1016/j.cell.2010.08.014 PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    McCarthy RC, Park YH, Kosman DJ (2014) sAPP modulates iron efflux from brain microvascular endothelial cells by stabilizing the ferrous iron exporter ferroportin. EMBO Rep 15(7):809–815PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Ayton S, Lei P, Hare DJ, Duce JA, George JL, Adlard PA, McLean C, Rogers JT, Cherny RA, Finkelstein DI, Bush AI (2015) Parkinson’s disease iron deposition caused by nitric oxide-induced loss of beta-amyloid precursor protein. J Neurosci 35(8):3591–3597. doi: 10.1523/JNEUROSCI.3439-14.2015 PubMedCrossRefGoogle Scholar
  72. 72.
    Morris CM, Candy JM, Keith AB, Oakley AE, Taylor GA, Pullen RG, Bloxham CA, Gocht A, Edwardson JA (1992) Brain iron homeostasis. J Inorg Biochem 47(3-4):257–265PubMedCrossRefGoogle Scholar
  73. 73.
    Levi S, Santambrogio P, Cozzi A, Rovida E, Corsi B, Tamborini E, Spada S, Albertini A, Arosio P (1994) The role of the L-chain in ferritin iron incorporation. Studies of homo and heteropolymers. J Mol Biol 238(5):649–654. doi: 10.1006/jmbi.1994.1325 PubMedCrossRefGoogle Scholar
  74. 74.
    Lawson DM, Treffry A, Artymiuk PJ, Harrison PM, Yewdall SJ, Luzzago A, Cesareni G, Levi S, Arosio P (1989) Identification of the ferroxidase centre in ferritin. FEBS Lett 254(1-2):207–210PubMedCrossRefGoogle Scholar
  75. 75.
    Cheepsunthorn P, Palmer C, Connor JR (1998) Cellular distribution of ferritin subunits in postnatal rat brain. J Comp Neurol 400(1):73–86. doi: 10.1002/(SICI)1096-9861(19981012)400:1<73::AID-CNE5>3.0.CO;2-Q PubMedCrossRefGoogle Scholar
  76. 76.
    Connor JR, Boeshore KL, Benkovic SA, Menzies SL (1994) Isoforms of ferritin have a specific cellular distribution in the brain. J Neurosci Res 37(4):461–465. doi: 10.1002/jnr.490370405 PubMedCrossRefGoogle Scholar
  77. 77.
    Snyder AM, Connor JR (2009) Iron, the substantia nigra and related neurological disorders. Biochim Biophys Acta 1790(7):606–614. doi: 10.1016/j.bbagen.2008.08.005 PubMedCrossRefGoogle Scholar
  78. 78.
    Han J, Day JR, Connor JR, Beard JL (2002) H and L ferritin subunit mRNA expression differs in brains of control and iron-deficient rats. J Nutr 132(9):2769–2774PubMedGoogle Scholar
  79. 79.
    Connor JR, Boyer PJ, Menzies SL, Dellinger B, Allen RP, Ondo WG, Earley CJ (2003) Neuropathological examination suggests impaired brain iron acquisition in restless legs syndrome. Neurology 61(3):304–309PubMedCrossRefGoogle Scholar
  80. 80.
    Double KL, Gerlach M, Schunemann V, Trautwein AX, Zecca L, Gallorini M, Youdim MB, Riederer P, Ben-Shachar D (2003) Iron-binding characteristics of neuromelanin of the human substantia nigra. Biochem Pharmacol 66(3):489–494PubMedCrossRefGoogle Scholar
  81. 81.
    Tribl F, Asan E, Arzberger T, Tatschner T, Langenfeld E, Meyer HE, Bringmann G, Riederer P, Gerlach M, Marcus K (2009) Identification of L-ferritin in neuromelanin granules of the human substantia nigra: a targeted proteomics approach. Mol Cell Proteomics 8(8):1832–1838. doi: 10.1074/mcp.M900006-MCP200 PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Devos D, Moreau C, Devedjian JC, Kluza J, Petrault M, Laloux C, Jonneaux A, Ryckewaert G, Garcon G, Rouaix N, Duhamel A, Jissendi P, Dujardin K, Auger F, Ravasi L, Hopes L, Grolez G, Firdaus W, Sablonniere B, Strubi-Vuillaume I, Zahr N, Destee A, Corvol JC, Poltl D, Leist M, Rose C, Defebvre L, Marchetti P, Cabantchik ZI, Bordet R (2014) Targeting chelatable iron as a therapeutic modality in Parkinson’s disease. Antioxid Redox Signal 21(2):195–210. doi: 10.1089/ars.2013.5593 PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Park CH, Valore EV, Waring AJ, Ganz T (2001) Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem 276(11):7806–7810. doi: 10.1074/jbc.M008922200 PubMedCrossRefGoogle Scholar
  84. 84.
    Nicolas G, Viatte L, Bennoun M, Beaumont C, Kahn A, Vaulont S (2002) Hepcidin, a new iron regulatory peptide. Blood Cells Mol Dis 29(3):327–335PubMedCrossRefGoogle Scholar
  85. 85.
    Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, Ganz T, Kaplan J (2004) Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 306(5704):2090–2093. doi: 10.1126/science.1104742 PubMedCrossRefGoogle Scholar
  86. 86.
    Knutson MD, Oukka M, Koss LM, Aydemir F, Wessling-Resnick M (2005) Iron release from macrophages after erythrophagocytosis is up-regulated by ferroportin 1 overexpression and down-regulated by hepcidin. Proc Natl Acad Sci U S A 102(5):1324–1328. doi: 10.1073/pnas.0409409102 PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Wang SM, Fu LJ, Duan XL, Crooks DR, Yu P, Qian ZM, Di XJ, Li J, Rouault TA, Chang YZ (2009) Role of hepcidin in murine brain iron metabolism. Cell Mol Life Sci. doi: 10.1007/s00018-009-0167-3
  88. 88.
    Zechel S, Huber-Wittmer K, Von B, Halbach O (2006) Distribution of the iron-regulating protein hepcidin in the murine central nervous system. J Neurosci Res 84(4):790–800. doi: 10.1002/jnr.20991 PubMedCrossRefGoogle Scholar
  89. 89.
    Du F, Qian ZM, Luo Q, Yung WH, Ke Y (2014) Hepcidin Suppresses Brain Iron Accumulation by Downregulating Iron Transport Proteins in Iron-Overloaded Rats. Mol Neurobiol. doi: 10.1007/s12035-014-8847-x
  90. 90.
    Foot NJ, Dalton HE, Shearwin-Whyatt LM, Dorstyn L, Tan SS, Yang B, Kumar S (2008) Regulation of the divalent metal ion transporter DMT1 and iron homeostasis by a ubiquitin-dependent mechanism involving Ndfips and WWP2. Blood 112(10):4268–4275. doi: 10.1182/blood-2008-04-150953 PubMedCrossRefGoogle Scholar
  91. 91.
    Guo B, Yu Y, Leibold EA (1994) Iron regulates cytoplasmic levels of a novel iron-responsive element-binding protein without aconitase activity. J Biol Chem 269(39):24252–24260PubMedGoogle Scholar
  92. 92.
    Henderson BR, Kuhn LC (1995) Differential modulation of the RNA-binding proteins IRP-1 and IRP-2 in response to iron. IRP-2 inactivation requires translation of another protein. J Biol Chem 270(35):20509–20515PubMedCrossRefGoogle Scholar
  93. 93.
    Regan RF, Li Z, Chen M, Zhang X, Chen-Roetling J (2008) Iron regulatory proteins increase neuronal vulnerability to hydrogen peroxide. Biochem Biophys Res Commun 375(1):6–10. doi: 10.1016/j.bbrc.2008.07.061 PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Richardson DR, Lane DJ, Becker EM, Huang ML, Whitnall M, Suryo Rahmanto Y, Sheftel AD, Ponka P (2010) Mitochondrial iron trafficking and the integration of iron metabolism between the mitochondrion and cytosol. Proc Natl Acad Sci U S A 107(24):10775–10782. doi: 10.1073/pnas.0912925107 PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Yanatori I, Tabuchi M, Kawai Y, Yasui Y, Akagi R, Kishi F (2010) Heme and non-heme iron transporters in non-polarized and polarized cells. BMC Cell Biol 11:39. doi: 10.1186/1471-2121-11-39 PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Zhang Y, Mikhael M, Xu D, Li Y, Soe-Lin S, Ning B, Li W, Nie G, Zhao Y, Ponka P (2010a) Lysosomal proteolysis is the primary degradation pathway for cytosolic ferritin and cytosolic ferritin degradation is necessary for iron exit. Antioxid Redox Signal 13(7):999–1009. doi: 10.1089/ars.2010.3129 PubMedCrossRefGoogle Scholar
  97. 97.
    Zhang J, Zhang Y, Wang J, Cai P, Luo C, Qian Z, Dai Y, Feng H (2010b) Characterizing iron deposition in Parkinson's disease using susceptibility-weighted imaging: an in vivo MR study. Brain Res 2010; 1330:124--130Google Scholar
  98. 98.
    Garrick MD, Zhao L, Roth JA, Jiang H, Feng J, Foot NJ, Dalton H, Kumar S, Garrick LM (2012) Isoform specific regulation of divalent metal (ion) transporter (DMT1) by proteasomal degradation. Biometals 25(4):787–793. doi: 10.1007/s10534-012-9522-1 PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Song W, Patel A, Qureshi HY, Han D, Schipper HM, Paudel HK (2009) The Parkinson disease-associated A30P mutation stabilizes alpha-synuclein against proteasomal degradation triggered by heme oxygenase-1 over-expression in human neuroblastoma cells. J Neurochem 110(2):719–733. doi: 10.1111/j.1471-4159.2009.06165.x PubMedCrossRefGoogle Scholar
  100. 100.
    Dong XP, Cheng X, Mills E, Delling M, Wang F, Kurz T, Xu H (2008) The type IV mucolipidosis-associated protein TRPML1 is an endolysosomal iron release channel. Nature 455(7215):992–996. doi: 10.1038/nature07311 PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Nilius B, Owsianik G, Voets T, Peters JA (2007) Transient receptor potential cation channels in disease. Physiol Rev 87(1):165–217. doi: 10.1152/physrev.00021.2006 PubMedCrossRefGoogle Scholar
  102. 102.
    Qian F, Noben-Trauth K (2005) Cellular and molecular function of mucolipins (TRPML) and polycystin 2 (TRPP2). Pflugers Arch 451(1):277–285. doi: 10.1007/s00424-005-1469-4 PubMedCrossRefGoogle Scholar
  103. 103.
    Sun M, Goldin E, Stahl S, Falardeau JL, Kennedy JC, Acierno JS Jr, Bove C, Kaneski CR, Nagle J, Bromley MC, Colman M, Schiffmann R, Slaugenhaupt SA (2000) Mucolipidosis type IV is caused by mutations in a gene encoding a novel transient receptor potential channel. Hum Mol Genet 9(17):2471–2478PubMedCrossRefGoogle Scholar
  104. 104.
    Napier I, Ponka P, Richardson DR (2005) Iron trafficking in the mitochondrion: novel pathways revealed by disease. Blood 105(5):1867–1874. doi: 10.1182/blood-2004-10-3856 PubMedCrossRefGoogle Scholar
  105. 105.
    Huang XP, O’Brien PJ, Templeton DM (2006) Mitochondrial involvement in genetically determined transition metal toxicity I. Iron toxicity. Chem Biol Interact 163(1-2):68–76. doi: 10.1016/j.cbi.2006.05.007 PubMedCrossRefGoogle Scholar
  106. 106.
    Mastroberardino PG, Hoffman EK, Horowitz MP, Betarbet R, Taylor G, Cheng D, Na HM, Gutekunst CA, Gearing M, Trojanowski JQ, Anderson M, Chu CT, Peng J, Greenamyre JT (2009) A novel transferrin/TfR2-mediated mitochondrial iron transport system is disrupted in Parkinson’s disease. Neurobiol Dis 34(3):417–431. doi: 10.1016/j.nbd.2009.02.009 PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Rhodes SL, Buchanan DD, Ahmed I, Taylor KD, Loriot MA, Sinsheimer JS, Bronstein JM, Elbaz A, Mellick GD, Rotter JI, Ritz B (2014) Pooled analysis of iron-related genes in Parkinson’s disease: association with transferrin. Neurobiol Dis 62:172–178. doi: 10.1016/j.nbd.2013.09.019 PubMedCrossRefGoogle Scholar
  108. 108.
    Levi S, Corsi B, Bosisio M, Invernizzi R, Volz A, Sanford D, Arosio P, Drysdale J (2001) A human mitochondrial ferritin encoded by an intronless gene. J Biol Chem 276(27):24437–24440. doi: 10.1074/jbc.C100141200 PubMedCrossRefGoogle Scholar
  109. 109.
    Jin L, Wang J, Zhao L, Jin H, Fei G, Zhang Y, Zeng M, Zhong C (2011) Decreased serum ceruloplasmin levels characteristically aggravate nigral iron deposition in Parkinson’s disease. Brain 134(Pt 1):50–58. doi: 10.1093/brain/awq319 PubMedCrossRefGoogle Scholar
  110. 110.
    Missirlis F, Holmberg S, Georgieva T, Dunkov BC, Rouault TA, Law JH (2006) Characterization of mitochondrial ferritin in Drosophila. Proc Natl Acad Sci U S A 103(15):5893–5898. doi: 10.1073/pnas.0601471103 PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Shi ZH, Nie G, Duan XL, Rouault T, Wu WS, Ning B, Zhang N, Chang YZ, Zhao BL (2010) Neuroprotective mechanism of mitochondrial ferritin on 6-hydroxydopamine-induced dopaminergic cell damage: implication for neuroprotection in Parkinson’s disease. Antioxid Redox Signal 13(6):783–796. doi: 10.1089/ars.2009.3018 PubMedCrossRefGoogle Scholar
  112. 112.
    Bandyopadhyay S, Cahill C, Balleidier A, Huang C, Lahiri DK, Huang X, Rogers JT (2013) Novel 5’ untranslated region directed blockers of iron-regulatory protein-1 dependent amyloid precursor protein translation: implications for down syndrome and Alzheimer’s disease. PLoS One 8(7):e65978. doi: 10.1371/journal.pone.0065978 PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Santambrogio P, Biasiotto G, Sanvito F, Olivieri S, Arosio P, Levi S (2007) Mitochondrial ferritin expression in adult mouse tissues. J Histochem Cytochem 55(11):1129–1137Google Scholar
  114. 114.
    Bou-Abdallah F, Santambrogio P, Levi S, Arosio P, Chasteen ND (2005) Unique iron binding and oxidation properties of human mitochondrial ferritin: a comparative analysis with Human H-chain ferritin. J Mol Biol 347(3):543–554. doi: 10.1016/j.jmb.2005.01.007 PubMedCrossRefGoogle Scholar
  115. 115.
    Nie G, Sheftel AD, Kim SF, Ponka P (2005) Overexpression of mitochondrial ferritin causes cytosolic iron depletion and changes cellular iron homeostasis. Blood 105(5):2161–2167. doi: 10.1182/blood-2004-07-2722 PubMedCrossRefGoogle Scholar
  116. 116.
    Wu WS, Zhao YS, Shi ZH, Chang SY, Nie GJ, Duan XL, Zhao SM, Wu Q, Yang ZL, Zhao BL, Chang YZ (2013) Mitochondrial ferritin attenuates beta-amyloid-induced neurotoxicity: reduction in oxidative damage through the Erk/P38 mitogen-activated protein kinase pathways. Antioxid Redox Signal 18(2):158–169. doi: 10.1089/ars.2011.4285 PubMedCrossRefGoogle Scholar
  117. 117.
    Schipper HM (2004) Heme oxygenase expression in human central nervous system disorders. Free Radic Biol Med 37(12):1995–2011. doi: 10.1016/j.freeradbiomed.2004.09.015 PubMedCrossRefGoogle Scholar
  118. 118.
    Mehindate K, Sahlas DJ, Frankel D, Mawal Y, Liberman A, Corcos J, Dion S, Schipper HM (2001) Proinflammatory cytokines promote glial heme oxygenase-1 expression and mitochondrial iron deposition: implications for multiple sclerosis. J Neurochem 77(5):1386–1395PubMedCrossRefGoogle Scholar
  119. 119.
    Lavrovsky Y, Drummond GS, Abraham NG (1996) Downregulation of the human heme oxygenase gene by glucocorticoids and identification of 56b regulatory elements. Biochem Biophys Res Commun 218(3):759–765. doi: 10.1006/bbrc.1996.0135 PubMedCrossRefGoogle Scholar
  120. 120.
    Broekemeier KM, Pfeiffer DR (1995) Inhibition of the mitochondrial permeability transition by cyclosporin A during long time frame experiments: relationship between pore opening and the activity of mitochondrial phospholipases. Biochemistry 34(50):16440–16449PubMedCrossRefGoogle Scholar
  121. 121.
    Petronilli V, Cola C, Massari S, Colonna R, Bernardi P (1993) Physiological effectors modify voltage sensing by the cyclosporin A-sensitive permeability transition pore of mitochondria. J Biol Chem 268(29):21939–21945PubMedGoogle Scholar
  122. 122.
    Song L, Song W, Schipper HM (2007) Astroglia overexpressing heme oxygenase-1 predispose co-cultured PC12 cells to oxidative injury. J Neurosci Res 85(10):2186–2195. doi: 10.1002/jnr.21367 PubMedCrossRefGoogle Scholar
  123. 123.
    Riederer P, Sofic E, Rausch WD, Schmidt B, Reynolds GP, Jellinger K, Youdim MB (1989) Transition metals, ferritin, glutathione, and ascorbic acid in parkinsonian brains. J Neurochem 52(2):515–520Google Scholar
  124. 124.
    Mann VM, Cooper JM, Daniel SE, Srai K, Jenner P, Marsden CD, Schapira AH (1994) Complex I, iron, and ferritin in Parkinson's disease substantia nigra. Ann Neurol 36(6):876–881Google Scholar
  125. 125.
    Griffiths PD, Dobson BR, Jones GR, Clarke DT (1999) Iron in the basal ganglia in Parkinson's disease. An in vitro study using extended X-ray absorption fine structure and cryo-electron microscopy. Brain 122(4):667–673Google Scholar
  126. 126.
    Jellinger K, Kienzl E, Rumpelmair G, Riederer P, Stachelberger H, Ben-Shachar D, Youdim MB (1992) Iron-melanin complex in substantia nigra of parkinsonian brains: an x-ray microanalysis. J Neurochem 59(3):1168–1171Google Scholar
  127. 127.
    Berg, D., Roggendorf, W., Schroder, U., Klein, R., Tatschner, T., Benz, P., Tucha, O., Preier, M., Lange, K. W., Reiners, K., Gerlach, M. and Becker, G. (2002) Echogenicity of the substantia nigra: association with increased iron content and marker for susceptibility to nigrostriatal injury. Arch Neurol 59:999–1005Google Scholar
  128. 128.
    Kaur D, Yantiri F, Rajagopalan S, Kumar J, Mo JQ, Boonplueang R, Viswanath V, Jacobs R, Yang L, Beal MF, DiMonte D, Volitaskis I, Ellerby L, Cherny RA, Bush AI, Andersen JK (2003) Genetic or pharmacological iron chelation prevents MPTP-induced neurotoxicity in vivo: a novel therapy for Parkinson’s disease. Neuron 37(6):899–909PubMedCrossRefGoogle Scholar
  129. 129.
    Gaeta A, Hider RC (2005) The crucial role of metal ions in neurodegeneration: the basis for a promising therapeutic strategy. Br J Pharmacol 146(8):1041–1059. doi: 10.1038/sj.bjp.0706416 PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Zhu W, Xie W, Pan T, Xu P, Fridkin M, Zheng H, Jankovic J, Youdim MB, Le W (2007) Prevention and restoration of lactacystin-induced nigrostriatal dopamine neuron degeneration by novel brain-permeable iron chelators. FASEB J 21(14):3835–3844. doi: 10.1096/fj.07-8386com PubMedCrossRefGoogle Scholar
  131. 131.
    Youdim MB (2006) My love with monoamine oxidase, iron and Parkinson’s disease. J Neural Transm Suppl 71:V–IXGoogle Scholar
  132. 132.
    Ayton S, Lei P, Adlard PA, Volitakis I, Cherny RA, Bush AI, Finkelstein DI (2014) Iron accumulation confers neurotoxicity to a vulnerable population of nigral neurons: implications for Parkinson’s disease. Mol Neurodegener 9:27. doi: 10.1186/1750-1326-9-27 PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Sofic E, Riederer P, Heinsen H, Beckmann H, Reynolds GP, Hebenstreit G, Youdim MB (1988) Increased iron (III) and total iron content in post mortem substantia nigra of parkinsonian brain. J Neural Transm 74(3):199–205PubMedCrossRefGoogle Scholar
  134. 134.
    Sofic E, Paulus W, Jellinger K, Riederer P, Youdim MB (1991) Selective increase of iron in substantia nigra zona compacta of parkinsonian brains. J Neurochem 56(3):978–982PubMedCrossRefGoogle Scholar
  135. 135.
    Dexter DT, Carayon A, Javoy-Agid F, Agid Y, Wells FR, Daniel SE, Lees AJ, Jenner P, Marsden CD (1991) Alterations in the levels of iron, ferritin and other trace metals in Parkinson’s disease and other neurodegenerative diseases affecting the basal ganglia. Brain 114(Pt 4):1953–1975PubMedCrossRefGoogle Scholar
  136. 136.
    Drayer BP, Olanow W, Burger P, Johnson GA, Herfkens R, Riederer S (1986) Parkinson plus syndrome: diagnosis using high field MR imaging of brain iron. Radiology 159(2):493–498PubMedCrossRefGoogle Scholar
  137. 137.
    Ryvlin P, Broussolle E, Piollet H, Viallet F, Khalfallah Y, Chazot G (1995) Magnetic resonance imaging evidence of decreased putamenal iron content in idiopathic Parkinson’s disease. Arch Neurol 52(6):583–588PubMedCrossRefGoogle Scholar
  138. 138.
    Good PF, Olanow CW, Perl DP (1992) Neuromelanin-containing neurons of the substantia nigra accumulate iron and aluminum in Parkinson’s disease: a LAMMA study. Brain Res 593(2):343–346PubMedCrossRefGoogle Scholar
  139. 139.
    Bandyopadhyay S, Rogers JT (2014) Alzheimer’s disease therapeutics targeted to the control of amyloid precursor protein translation: maintenance of brain iron homeostasis. Biochem Pharmacol 88(4):486–494. doi: 10.1016/j.bcp.2014.01.032 PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Rossi M, Ruottinen H, Soimakallio S, Elovaara I, Dastidar P (2013) Clinical MRI for iron detection in Parkinson’s disease. Clin Imaging 37(4):631–636. doi: 10.1016/j.clinimag.2013.02.001 PubMedCrossRefGoogle Scholar
  141. 141.
    Wang C, Fan G, Xu K, Wang S (2013) Quantitative assessment of iron deposition in the midbrain using 3D-enhanced T2 star weighted angiography (ESWAN): a preliminary cross-sectional study of 20 Parkinson’s disease patients. Magn Reson Imaging 31(7):1068–1073. doi: 10.1016/j.mri.2013.04.015 PubMedCrossRefGoogle Scholar
  142. 142.
    Barbosa JH, Santos AC, Tumas V, Liu M, Zheng W, Haacke EM, Salmon CE (2015) Quantifying brain iron deposition in patients with Parkinson’s disease using quantitative susceptibility mapping, R2 and R2. Magn Reson Imaging 33(5):559–565. doi: 10.1016/j.mri.2015.02.021 PubMedCrossRefGoogle Scholar
  143. 143.
    Berg D (2006) In vivo detection of iron and neuromelanin by transcranial sonography--a new approach for early detection of substantia nigra damage. J Neural Transm 113(6):775–780. doi: 10.1007/s00702-005-0447-5 PubMedCrossRefGoogle Scholar
  144. 144.
    Wallis LI, Paley MN, Graham JM, Grunewald RA, Wignall EL, Joy HM, Griffiths PD (2008) MRI assessment of basal ganglia iron deposition in Parkinson’s disease. J Magn Reson Imaging 28(5):1061–1067. doi: 10.1002/jmri.21563 PubMedCrossRefGoogle Scholar
  145. 145.
    Pavese N, Brooks DJ (2008) Imaging neurodegeneration in Parkinson’s disease. Biochimica et biophysica acta. doi:  10.1016/j.bbadis.2008.10.003
  146. 146.
    Martin WR, Wieler M, Gee M (2008) Midbrain iron content in early Parkinson disease: a potential biomarker of disease status. Neurology 70(16 Pt 2):1411–1417. doi: 10.1212/01.wnl.0000286384.31050.b5 PubMedCrossRefGoogle Scholar
  147. 147.
    Pavese N, Brooks DJ (2009) Imaging neurodegeneration in Parkinson’s disease. Biochim Biophys Acta 1792(7):722–729. doi: 10.1016/j.bbadis.2008.10.003 PubMedCrossRefGoogle Scholar
  148. 148.
    Wu SF, Zhu ZF, Kong Y, Zhang HP, Zhou GQ, Jiang QT, Meng XP (2014) Assessment of cerebral iron content in patients with Parkinson’s disease by the susceptibility-weighted MRI. Eur Rev Med Pharmacol Sci 18(18):2605–2608PubMedGoogle Scholar
  149. 149.
    Yu X, Du T, Song N, He Q, Shen Y, Jiang H, Xie J (2013) Decreased iron levels in the temporal cortex in postmortem human brains with Parkinson disease. Neurology 80(5):492–495. doi: 10.1212/WNL.0b013e31827f0ebb PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    Gorell JM, Johnson CC, Rybicki BA, Peterson EL, Kortsha GX, Brown GG, Richardson RJ (1999) Occupational exposure to manganese, copper, lead, iron, mercury and zinc and the risk of Parkinson’s disease. Neurotoxicology 20(2-3):239–247PubMedGoogle Scholar
  151. 151.
    Powers KM, Smith-Weller T, Franklin GM, Longstreth WT Jr, Swanson PD, Checkoway H (2003) Parkinson’s disease risks associated with dietary iron, manganese, and other nutrient intakes. Neurology 60(11):1761–1766PubMedCrossRefGoogle Scholar
  152. 152.
    Logroscino G, Gao X, Chen H, Wing A, Ascherio A (2008) Dietary iron intake and risk of Parkinson’s disease. Am J Epidemiol 168(12):1381–1388. doi: 10.1093/aje/kwn273 PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Powers KM, Smith-Weller T, Franklin GM, Longstreth WT Jr, Swanson PD, Checkoway H (2009) Dietary fats, cholesterol and iron as risk factors for Parkinson’s disease. Parkinsonism Relat Disord 15(1):47–52. doi: 10.1016/j.parkreldis.2008.03.002 PubMedCrossRefGoogle Scholar
  154. 154.
    Ma ZG, Wang J, Jiang H, Liu TW, Xie JX (2007) Myricetin reduces 6-hydroxydopamine-induced dopamine neuron degeneration in rats. Neuroreport 18(11):1181–1185. doi: 10.1097/WNR.0b013e32821c51fe PubMedCrossRefGoogle Scholar
  155. 155.
    Wang J, Jiang H, Xie JX (2004) Time dependent effects of 6-OHDA lesions on iron level and neuronal loss in rat nigrostriatal system. Neurochem Res 29(12):2239–2243PubMedCrossRefGoogle Scholar
  156. 156.
    Wang J, Xu HM, Yang HD, Du XX, Jiang H, Xie JX (2009) Rg1 reduces nigral iron levels of MPTP-treated C57BL6 mice by regulating certain iron transport proteins. Neurochem Int 54(1):43–48. doi: 10.1016/j.neuint.2008.10.003 PubMedCrossRefGoogle Scholar
  157. 157.
    Youdim MB (2003) What have we learnt from CDNA microarray gene expression studies about the role of iron in MPTP induced neurodegeneration and Parkinson’s disease? J Neural Transm Suppl 65:73–88CrossRefGoogle Scholar
  158. 158.
    Youdim MB, Grunblatt E, Levites Y, Maor G, Mandel S (2002) Early and late molecular events in neurodegeneration and neuroprotection in Parkinson’s disease MPTP model as assessed by cDNA microarray; the role of iron. Neurotox Res 4(7-8):679–689. doi: 10.1080/1029842021000045507 PubMedCrossRefGoogle Scholar
  159. 159.
    Hare DJ, Adlard PA, Doble PA, Finkelstein DI (2013) Metallobiology of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity. Metallomics 5(2):91–109. doi: 10.1039/c2mt20164j PubMedCrossRefGoogle Scholar
  160. 160.
    Zhang J, Stanton DM, Nguyen XV, Liu M, Zhang Z, Gash D, Bing G (2005) Intrapallidal lipopolysaccharide injection increases iron and ferritin levels in glia of the rat substantia nigra and induces locomotor deficits. Neuroscience 135(3):829–838. doi: 10.1016/j.neuroscience.2005.06.049 PubMedCrossRefGoogle Scholar
  161. 161.
    Peng J, Peng L, Stevenson FF, Doctrow SR, Andersen JK (2007) Iron and paraquat as synergistic environmental risk factors in sporadic Parkinson’s disease accelerate age-related neurodegeneration. J Neurosci 27(26):6914–6922. doi: 10.1523/JNEUROSCI.1569-07.2007 PubMedCrossRefGoogle Scholar
  162. 162.
    Peng J, Stevenson FF, Oo ML, Andersen JK (2009) Iron-enhanced paraquat-mediated dopaminergic cell death due to increased oxidative stress as a consequence of microglial activation. Free Radic Biol Med 46(2):312–320. doi: 10.1016/j.freeradbiomed.2008.10.045 PubMedCrossRefGoogle Scholar
  163. 163.
    Junxia X, Hong J, Wenfang C, Ming Q (2003) Dopamine release rather than content in the caudate putamen is associated with behavioral changes in the iron rat model of Parkinson’s disease. Exp Neurol 182(2):483–489PubMedCrossRefGoogle Scholar
  164. 164.
    Ben-Shachar D, Youdim MB (1991) Intranigral iron injection induces behavioral and biochemical “parkinsonism” in rats. J Neurochem 57(6):2133–2135PubMedCrossRefGoogle Scholar
  165. 165.
    Jiang H, Song N, Wang J, Ren LY, Xie JX (2007) Peripheral iron dextran induced degeneration of dopaminergic neurons in rat substantia nigra. Neurochem Int 51(1):32–36. doi: 10.1016/j.neuint.2007.03.006 PubMedCrossRefGoogle Scholar
  166. 166.
    Jiang H, Luan Z, Wang J, Xie J (2006) Neuroprotective effects of iron chelator Desferal on dopaminergic neurons in the substantia nigra of rats with iron-overload. Neurochem Int 49(6):605–609. doi: 10.1016/j.neuint.2006.04.015 PubMedCrossRefGoogle Scholar
  167. 167.
    Fredriksson A, Schroder N, Eriksson P, Izquierdo I, Archer T (1999) Neonatal iron exposure induces neurobehavioural dysfunctions in adult mice. Toxicol Appl Pharmacol 159(1):25–30. doi: 10.1006/taap.1999.8711 PubMedCrossRefGoogle Scholar
  168. 168.
    Kaur D, Peng J, Chinta SJ, Rajagopalan S, Di Monte DA, Cherny RA, Andersen JK (2007) Increased murine neonatal iron intake results in Parkinson-like neurodegeneration with age. Neurobiol Aging 28(6):907–913. doi: 10.1016/j.neurobiolaging.2006.04.003 PubMedCrossRefGoogle Scholar
  169. 169.
    Faucheux BA, Hirsch EC, Villares J, Selimi F, Mouatt-Prigent A, Javoy-Agid F, Hauw JJ, Agid Y (1993) Distribution of 125I-ferrotransferrin binding sites in the mesencephalon of control subjects and patients with Parkinson's disease. J Neurochem 60: 2338–2341Google Scholar
  170. 170.
    Faucheux BA, Hauw JJ, Agid Y, Hirsch EC (1997) The density of [125I]-transferrin binding sites on perikarya of melanized neurons of the substantia nigra is decreased in Parkinson’s disease. Brain Res 749(1):170–174PubMedCrossRefGoogle Scholar
  171. 171.
    Kalivendi SV, Kotamraju S, Cunningham S, Shang T, Hillard CJ, Kalyanaraman B (2003) 1-Methyl-4-phenylpyridinium (MPP+)-induced apoptosis and mitochondrial oxidant generation: role of transferrin-receptor-dependent iron and hydrogen peroxide. Biochem J 371(Pt 1):151–164. doi: 10.1042/BJ20021525 PubMedPubMedCentralCrossRefGoogle Scholar
  172. 172.
    Kaur D, Lee D, Ragapolan S, Andersen JK (2009) Glutathione depletion in immortalized midbrain-derived dopaminergic neurons results in increases in the labile iron pool: implications for Parkinson’s disease. Free Radic Biol Med 46(5):593–598. doi: 10.1016/j.freeradbiomed.2008.11.012 PubMedCrossRefGoogle Scholar
  173. 173.
    Lee DW, Andersen JK (2010) Iron elevations in the aging Parkinsonian brain: a consequence of impaired iron homeostasis? J Neurochem 112(2):332–339. doi: 10.1111/j.1471-4159.2009.06470.x PubMedCrossRefGoogle Scholar
  174. 174.
    Huang E, Ong WY, Connor JR (2004) Distribution of divalent metal transporter-1 in the monkey basal ganglia. Neuroscience 128(3):487–496. doi: 10.1016/j.neuroscience.2004.06.055 PubMedCrossRefGoogle Scholar
  175. 175.
    Salazar J, Mena N, Hunot S, Prigent A, Alvarez-Fischer D, Arredondo M, Duyckaerts C, Sazdovitch V, Zhao L, Garrick LM, Nunez MT, Garrick MD, Raisman-Vozari R, Hirsch EC (2008) Divalent metal transporter 1 (DMT1) contributes to neurodegeneration in animal models of Parkinson’s disease. Proc Natl Acad Sci U S A 105(47):18578–18583. doi: 10.1073/pnas.0804373105 PubMedPubMedCentralCrossRefGoogle Scholar
  176. 176.
    Chung J, Wessling-Resnick M (2003) Molecular mechanisms and regulation of iron transport. Crit Rev Clin Lab Sci 40(2):151–182PubMedCrossRefGoogle Scholar
  177. 177.
    Gunshin H, Allerson CR, Polycarpou-Schwarz M, Rofts A, Rogers JT, Kishi F, Hentze MW, Rouault TA, Andrews NC, Hediger MA (2001) Iron-dependent regulation of the divalent metal ion transporter. FEBS Lett 509(2):309–316PubMedCrossRefGoogle Scholar
  178. 178.
    Song N, Wang J, Jiang H, Xie J Ferroportin 1 but not hephaestin contributes to iron accumulation in a cell model of Parkinson's disease. Free Radic Biol Med 48 (2):332-341. doi:  10.1016/j.freeradbiomed.2009.11.004
  179. 179.
    Jiang H, Qian ZM, Xie JX (2003) Increased DMT1 expression and iron content in MPTP-treated C57BL/6 mice. Sheng Li Xue Bao 55(5):571–576PubMedGoogle Scholar
  180. 180.
    Lee DW, Rajagopalan S, Siddiq A, Gwiazda R, Yang L, Beal MF, Ratan RR, Andersen JK (2009) Inhibition of prolyl hydroxylase protects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity: model for the potential involvement of the hypoxia-inducible factor pathway in Parkinson disease. J Biol Chem 284(42):29065–29076. doi: 10.1074/jbc.M109.000638 PubMedPubMedCentralCrossRefGoogle Scholar
  181. 181.
    Xu H, Jiang H, Wang J, Xie J (2009) Rg1 protects the MPP(+)-treated MES23.5 cells via attenuating DMT1 up-regulation and cellular iron uptake. Neuropharmacology. doi:  10.1016/j.neuropharm.2009.09.002
  182. 182.
    Zhang S, Wang J, Song N, Xie J, Jiang H (2009) Up-regulation of divalent metal transporter 1 is involved in 1-methyl-4-phenylpyridinium (MPP(+))-induced apoptosis in MES23.5 cells. Neurobiol Aging 30(9):1466–1476. doi: 10.1016/j.neurobiolaging.2007.11.025 PubMedCrossRefGoogle Scholar
  183. 183.
    Xu HM, Jiang H, Wang J, Luo B, Xie JX (2008) Over-expressed human divalent metal transporter 1 is involved in iron accumulation in MES23.5 cells. Neurochem Int 52(6):1044–1051. doi: 10.1016/j.neuint.2007.10.019 PubMedCrossRefGoogle Scholar
  184. 184.
    van der Strate BW, Beljaars L, Molema G, Harmsen MC, Meijer DK (2001) Antiviral activities of lactoferrin. Antiviral Res 52(3):225–239PubMedCrossRefGoogle Scholar
  185. 185.
    Fillebeen C, Ruchoux MM, Mitchell V, Vincent S, Benaissa M, Pierce A (2001) Lactoferrin is synthesized by activated microglia in the human substantia nigra and its synthesis by the human microglial CHME cell line is upregulated by tumor necrosis factor alpha or 1-methyl-4-phenylpyridinium treatment. Brain Res Mol Brain Res 96(1-2):103–113PubMedCrossRefGoogle Scholar
  186. 186.
    Fillebeen C, Mitchell V, Dexter D, Benaissa M, Beauvillain J, Spik G, Pierce A (1999) Lactoferrin is synthesized by mouse brain tissue and its expression is enhanced after MPTP treatment. Brain Res Mol Brain Res 72(2):183–194PubMedCrossRefGoogle Scholar
  187. 187.
    Leveugle B, Faucheux BA, Bouras C, Nillesse N, Spik G, Hirsch EC, Agid Y, Hof PR (1996) Cellular distribution of the iron-binding protein lactotransferrin in the mesencephalon of Parkinson’s disease cases. Acta Neuropathol 91(6):566–572PubMedCrossRefGoogle Scholar
  188. 188.
    Faucheux BA, Nillesse N, Damier P, Spik G, Mouatt-Prigent A, Pierce A, Leveugle B, Kubis N, Hauw JJ, Agid Y et al (1995) Expression of lactoferrin receptors is increased in the mesencephalon of patients with Parkinson disease. Proc Natl Acad Sci U S A 92(21):9603–9607PubMedPubMedCentralCrossRefGoogle Scholar
  189. 189.
    De Domenico I, Ward DM, di Patti MC, Jeong SY, David S, Musci G, Kaplan J (2007) Ferroxidase activity is required for the stability of cell surface ferroportin in cells expressing GPI-ceruloplasmin. EMBO J 26(12):2823–2831. doi: 10.1038/sj.emboj.7601735 PubMedPubMedCentralCrossRefGoogle Scholar
  190. 190.
    Hahn P, Qian Y, Dentchev T, Chen L, Beard J, Harris ZL, Dunaief JL (2004) Disruption of ceruloplasmin and hephaestin in mice causes retinal iron overload and retinal degeneration with features of age-related macular degeneration. Proc Natl Acad Sci U S A 101(38):13850–13855. doi: 10.1073/pnas.0405146101 PubMedPubMedCentralCrossRefGoogle Scholar
  191. 191.
    Kaneko K, Hineno A, Yoshida K, Ikeda S (2008) Increased vulnerability to rotenone-induced neurotoxicity in ceruloplasmin-deficient mice. Neurosci Lett 446(1):56–58. doi: 10.1016/j.neulet.2008.08.089 PubMedCrossRefGoogle Scholar
  192. 192.
    Bharucha KJ, Friedman JK, Vincent AS, Ross ED (2008) Lower serum ceruloplasmin levels correlate with younger age of onset in Parkinson’s disease. J Neurol 255(12):1957–1962. doi: 10.1007/s00415-009-0063-7 PubMedCrossRefGoogle Scholar
  193. 193.
    Mizuno S, Mihara T, Miyaoka T, Inagaki T, Horiguchi J (2005) CSF iron, ferritin and transferrin levels in restless legs syndrome. J Sleep Res 14(1):43–47. doi: 10.1111/j.1365-2869.2004.00403.x PubMedCrossRefGoogle Scholar
  194. 194.
    Tapryal N, Mukhopadhyay C, Das D, Fox PL, Mukhopadhyay CK (2009) Reactive oxygen species regulate ceruloplasmin by a novel mRNA decay mechanism involving its 3’-untranslated region: implications in neurodegenerative diseases. J Biol Chem 284(3):1873–1883. doi: 10.1074/jbc.M804079200 PubMedCrossRefGoogle Scholar
  195. 195.
    Ayton S, Lei P, Duce JA, Wong BX, Sedjahtera A, Adlard PA, Bush AI, Finkelstein DI (2013) Ceruloplasmin dysfunction and therapeutic potential for Parkinson disease. Ann Neurol 73(4):554–559. doi: 10.1002/ana.23817 PubMedCrossRefGoogle Scholar
  196. 196.
    Basso M, Giraudo S, Corpillo D, Bergamasco B, Lopiano L, Fasano M (2004) Proteome analysis of human substantia nigra in Parkinson’s disease. Proteomics 4(12):3943–3952. doi: 10.1002/pmic.200400848 PubMedCrossRefGoogle Scholar
  197. 197.
    Tsushima RG, Wickenden AD, Bouchard RA, Oudit GY, Liu PP, Backx PH (1999) Modulation of iron uptake in heart by L-type Ca2+ channel modifiers: possible implications in iron overload. Circ Res 84(11):1302–1309PubMedCrossRefGoogle Scholar
  198. 198.
    Oudit GY, Sun H, Trivieri MG, Koch SE, Dawood F, Ackerley C, Yazdanpanah M, Wilson GJ, Schwartz A, Liu PP, Backx PH (2003) L-type Ca2+ channels provide a major pathway for iron entry into cardiomyocytes in iron-overload cardiomyopathy. Nat Med 9(9):1187–1194. doi: 10.1038/nm920 PubMedCrossRefGoogle Scholar
  199. 199.
    De Waard M, Gurnett CA, Campbell KP (1996) Structural and functional diversity of voltage-activated calcium channels. Ion Channels 4:41–87PubMedCrossRefGoogle Scholar
  200. 200.
    Gaasch JA, Geldenhuys WJ, Lockman PR, Allen DD, Van der Schyf CJ (2007) Voltage-gated calcium channels provide an alternate route for iron uptake in neuronal cell cultures. Neurochem Res 32(10):1686–1693. doi: 10.1007/s11064-007-9313-1 PubMedCrossRefGoogle Scholar
  201. 201.
    Liss B, Roeper J (2001) ATP-sensitive potassium channels in dopaminergic neurons: transducers of mitochondrial dysfunction. News Physiol Sci 16:214–217PubMedGoogle Scholar
  202. 202.
    Liss B, Haeckel O, Wildmann J, Miki T, Seino S, Roeper J (2005) K-ATP channels promote the differential degeneration of dopaminergic midbrain neurons. Nat Neurosci 8(12):1742–1751. doi: 10.1038/nn1570 PubMedCrossRefGoogle Scholar
  203. 203.
    Schiemann J, Schlaudraff F, Klose V, Bingmer M, Seino S, Magill PJ, Zaghloul KA, Schneider G, Liss B, Roeper J (2012) K-ATP channels in dopamine substantia nigra neurons control bursting and novelty-induced exploration. Nat Neurosci 15(9):1272–1280. doi: 10.1038/nn.3185 PubMedPubMedCentralCrossRefGoogle Scholar
  204. 204.
    Li YX, Bertram R, Rinzel J (1996) Modeling N-methyl-D-aspartate-induced bursting in dopamine neurons. Neuroscience 71(2):397–410PubMedCrossRefGoogle Scholar
  205. 205.
    Chan CS, Guzman JN, Ilijic E, Mercer JN, Rick C, Tkatch T, Meredith GE, Surmeier DJ (2007) ‘Rejuvenation’ protects neurons in mouse models of Parkinson’s disease. Nature 447(7148):1081–1086. doi: 10.1038/nature05865 PubMedCrossRefGoogle Scholar
  206. 206.
    Guzman JN, Sanchez-Padilla J, Wokosin D, Kondapalli J, Ilijic E, Schumacker PT, Surmeier DJ (2010) Oxidant stress evoked by pacemaking in dopaminergic neurons is attenuated by DJ-1. Nature 468(7324):696–700. doi: 10.1038/nature09536 PubMedPubMedCentralCrossRefGoogle Scholar
  207. 207.
    Gunshin H, Mackenzie B, Berger UV, Gunshin Y, Romero MF, Boron WF, Nussberger S, Gollan JL, Hediger MA (1997) Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature 388(6641):482–488. doi: 10.1038/41343 PubMedCrossRefGoogle Scholar
  208. 208.
    Olanow CW (1992) An introduction to the free radical hypothesis in Parkinson’s disease. Ann Neurol 32(Suppl):S2–S9PubMedCrossRefGoogle Scholar
  209. 209.
    Cantuti-Castelvetri I, Shukitt-Hale B, Joseph JA (2003) Dopamine neurotoxicity: age-dependent behavioral and histological effects. Neurobiol Aging 24(5):697–706PubMedCrossRefGoogle Scholar
  210. 210.
    Sulzer D (2007) Multiple hit hypotheses for dopamine neuron loss in Parkinson’s disease. Trends Neurosci 30(5):244–250. doi: 10.1016/j.tins.2007.03.009 PubMedCrossRefGoogle Scholar
  211. 211.
    Barnham KJ, Masters CL, Bush AI (2004) Neurodegenerative diseases and oxidative stress. Nat Rev Drug Discov 3(3):205–214. doi: 10.1038/nrd1330 PubMedCrossRefGoogle Scholar
  212. 212.
    Lotharius J, Brundin P (2002) Pathogenesis of Parkinson’s disease: dopamine, vesicles and alpha-synuclein. Nat Rev Neurosci 3(12):932–942. doi: 10.1038/nrn983 PubMedCrossRefGoogle Scholar
  213. 213.
    Jimenez-Jimenez FJ, Molina JA, Aguilar MV, Meseguer I, Mateos-Vega CJ, Gonzalez-Munoz MJ, de Bustos F, Martinez-Salio A, Orti-Pareja M, Zurdo M, Martinez-Para MC (1998) Cerebrospinal fluid levels of transition metals in patients with Parkinson’s disease. J Neural Transm 105(4-5):497–505PubMedCrossRefGoogle Scholar
  214. 214.
    He Y, Thong PS, Lee T, Leong SK, Shi CY, Wong PT, Yuan SY, Watt F (1996) Increased iron in the substantia nigra of 6-OHDA induced parkinsonian rats: a nuclear microscopy study. Brain Res 735(1):149–153PubMedCrossRefGoogle Scholar
  215. 215.
    Popescu BF, George MJ, Bergmann U, Garachtchenko AV, Kelly ME, McCrea RP, Luning K, Devon RM, George GN, Hanson AD, Harder SM, Chapman LD, Pickering IJ, Nichol H (2009) Mapping metals in Parkinson’s and normal brain using rapid-scanning x-ray fluorescence. Phys Med Biol 54(3):651–663. doi: 10.1088/0031-9155/54/3/012 PubMedCrossRefGoogle Scholar
  216. 216.
    Fasano M, Bergamasco B, Lopiano L (2006) Modifications of the iron-neuromelanin system in Parkinson’s disease. J Neurochem 96(4):909–916. doi: 10.1111/j.1471-4159.2005.03638.x PubMedCrossRefGoogle Scholar
  217. 217.
    Berg D, Gerlach M, Youdim MB, Double KL, Zecca L, Riederer P, Becker G (2001) Brain iron pathways and their relevance to Parkinson’s disease. J Neurochem 79(2):225–236PubMedCrossRefGoogle Scholar
  218. 218.
    Zecca L, Zucca FA, Albertini A, Rizzio E, Fariello RG (2006) A proposed dual role of neuromelanin in the pathogenesis of Parkinson’s disease. Neurology 67(7 Suppl 2):S8–S11PubMedCrossRefGoogle Scholar
  219. 219.
    Zecca L, Casella L, Albertini A, Bellei C, Zucca FA, Engelen M, Zadlo A, Szewczyk G, Zareba M, Sarna T (2008) Neuromelanin can protect against iron-mediated oxidative damage in system modeling iron overload of brain aging and Parkinson’s disease. J Neurochem 106(4):1866–1875. doi: 10.1111/j.1471-4159.2008.05541.x PubMedGoogle Scholar
  220. 220.
    Zecca L, Fariello R, Riederer P, Sulzer D, Gatti A, Tampellini D (2002) The absolute concentration of nigral neuromelanin, assayed by a new sensitive method, increases throughout the life and is dramatically decreased in Parkinson’s disease. FEBS Lett 510(3):216–220PubMedCrossRefGoogle Scholar
  221. 221.
    Muller M, Leavitt BR (2014) Iron dysregulation in Huntington’s disease. J Neurochem 130(3):328–350. doi: 10.1111/jnc.12739 PubMedCrossRefGoogle Scholar
  222. 222.
    Forno LS, DeLanney LE, Irwin I, Di Monte D, Langston JW (1992) Astrocytes and Parkinson’s disease. Prog Brain Res 94:429–436PubMedCrossRefGoogle Scholar
  223. 223.
    Oshiro S, Kawamura K, Zhang C, Sone T, Morioka MS, Kobayashi S, Nakajima K (2008) Microglia and astroglia prevent oxidative stress-induced neuronal cell death: implications for aceruloplasminemia. Biochim Biophys Acta 1782(2):109–117. doi: 10.1016/j.bbadis.2007.12.002 PubMedCrossRefGoogle Scholar
  224. 224.
    Oshiro S, Kawahara M, Kuroda Y, Zhang C, Cai Y, Kitajima S, Shirao M (2000) Glial cells contribute more to iron and aluminum accumulation but are more resistant to oxidative stress than neuronal cells. Biochim Biophys Acta 1502(3):405–414PubMedCrossRefGoogle Scholar
  225. 225.
    Kress GJ, Dineley KE, Reynolds IJ (2002) The relationship between intracellular free iron and cell injury in cultured neurons, astrocytes, and oligodendrocytes. J Neurosci 22(14):5848–5855, 20026601 PubMedGoogle Scholar
  226. 226.
    Hoepken HH, Korten T, Robinson SR, Dringen R (2004) Iron accumulation, iron-mediated toxicity and altered levels of ferritin and transferrin receptor in cultured astrocytes during incubation with ferric ammonium citrate. J Neurochem 88(5):1194–1202PubMedCrossRefGoogle Scholar
  227. 227.
    Raicevic N, Mladenovic A, Perovic M, Harhaji L, Miljkovic D, Trajkovic V (2005) Iron protects astrocytes from 6-hydroxydopamine toxicity. Neuropharmacology 48(5):720–731. doi: 10.1016/j.neuropharm.2004.12.003 PubMedCrossRefGoogle Scholar
  228. 228.
    Burdo JR, Connor JR (2003) Brain iron uptake and homeostatic mechanisms: an overview. Biometals 16(1):63–75PubMedCrossRefGoogle Scholar
  229. 229.
    Bush AI (2000) Metals and neuroscience. Curr Opin Chem Biol 4(2):184–191PubMedCrossRefGoogle Scholar
  230. 230.
    Berg D, Hochstrasser H (2006) Iron metabolism in Parkinsonian syndromes. Mov Disord 21(9):1299–1310. doi: 10.1002/mds.21020 PubMedCrossRefGoogle Scholar
  231. 231.
    Reif DW (1992) Ferritin as a source of iron for oxidative damage. Free Radic Biol Med 12(5):417–427PubMedCrossRefGoogle Scholar
  232. 232.
    Kroemer G, Reed JC (2000) Mitochondrial control of cell death. Nat Med 6(5):513–519. doi: 10.1038/74994 PubMedCrossRefGoogle Scholar
  233. 233.
    Simpkins JW, Dykens JA (2008) Mitochondrial mechanisms of estrogen neuroprotection. Brain Res Rev 57(2):421–430. doi: 10.1016/j.brainresrev.2007.04.007 PubMedCrossRefGoogle Scholar
  234. 234.
    Ved R, Saha S, Westlund B, Perier C, Burnam L, Sluder A, Hoener M, Rodrigues CM, Alfonso A, Steer C, Liu L, Przedborski S, Wolozin B (2005) Similar patterns of mitochondrial vulnerability and rescue induced by genetic modification of alpha-synuclein, parkin, and DJ-1 in Caenorhabditis elegans. J Biol Chem 280(52):42655–42668. doi: 10.1074/jbc.M505910200 PubMedPubMedCentralCrossRefGoogle Scholar
  235. 235.
    Ikeda Y, Tsuji S, Satoh A, Ishikura M, Shirasawa T, Shimizu T (2008) Protective effects of astaxanthin on 6-hydroxydopamine-induced apoptosis in human neuroblastoma SH-SY5Y cells. J Neurochem 107(6):1730–1740. doi: 10.1111/j.1471-4159.2008.05743.x PubMedCrossRefGoogle Scholar
  236. 236.
    Weng Z, Signore AP, Gao Y, Wang S, Zhang F, Hastings T, Yin XM, Chen J (2007) Leptin protects against 6-hydroxydopamine-induced dopaminergic cell death via mitogen-activated protein kinase signaling. J Biol Chem 282(47):34479–34491. doi: 10.1074/jbc.M705426200 PubMedCrossRefGoogle Scholar
  237. 237.
    Double KL, Maywald M, Schmittel M, Riederer P, Gerlach M (1998) In vitro studies of ferritin iron release and neurotoxicity. J Neurochem 70(6):2492–2499PubMedCrossRefGoogle Scholar
  238. 238.
    Zhang X, Xie W, Qu S, Pan T, Wang X, Le W (2005) Neuroprotection by iron chelator against proteasome inhibitor-induced nigral degeneration. Biochem Biophys Res Commun 333(2):544–549. doi: 10.1016/j.bbrc.2005.05.150 PubMedCrossRefGoogle Scholar
  239. 239.
    McNaught KS, Mytilineou C, Jnobaptiste R, Yabut J, Shashidharan P, Jennert P, Olanow CW (2002) Impairment of the ubiquitin-proteasome system causes dopaminergic cell death and inclusion body formation in ventral mesencephalic cultures. J Neurochem 81(2):301–306PubMedCrossRefGoogle Scholar
  240. 240.
    Zhu W, Li X, Xie W, Luo F, Kaur D, Andersen JK, Jankovic J, Le W (2010) Genetic iron chelation protects against proteasome inhibition-induced dopamine neuron degeneration. Neurobiol Dis 37(2):307–313. doi: 10.1016/j.nbd.2009.09.024 PubMedCrossRefGoogle Scholar
  241. 241.
    Wang J, Fillebeen C, Chen G, Biederbick A, Lill R, Pantopoulos K (2007) Iron-dependent degradation of apo-IRP1 by the ubiquitin-proteasome pathway. Mol Cell Biol 27(7):2423–2430. doi: 10.1128/MCB.01111-06 PubMedPubMedCentralCrossRefGoogle Scholar
  242. 242.
    Jia W, Xu H, Du X, Jiang H, Xie J (2015) Ndfip1 attenuated 6-OHDA-induced iron accumulation via regulating the degradation of DMT1. Neurobiol Aging 36(2):1183–1193. doi: 10.1016/j.neurobiolaging.2014.10.021 PubMedCrossRefGoogle Scholar
  243. 243.
    Wood SJ, Wypych J, Steavenson S, Louis JC, Citron M, Biere AL (1999) alpha-synuclein fibrillogenesis is nucleation-dependent. Implications for the pathogenesis of Parkinson’s disease. J Biol Chem 274(28):19509–19512PubMedCrossRefGoogle Scholar
  244. 244.
    Kruger R, Kuhn W, Muller T, Woitalla D, Graeber M, Kosel S, Przuntek H, Epplen JT, Schols L, Riess O (1998) Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson’s disease. Nat Genet 18(2):106–108. doi: 10.1038/ng0298-106 PubMedCrossRefGoogle Scholar
  245. 245.
    Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R, Stenroos ES, Chandrasekharappa S, Athanassiadou A, Papapetropoulos T, Johnson WG, Lazzarini AM, Duvoisin RC, Di Iorio G, Golbe LI, Nussbaum RL (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 276(5321):2045–2047PubMedCrossRefGoogle Scholar
  246. 246.
    Hirsch EC, Brandel JP, Galle P, Javoy-Agid F, Agid Y (1991) Iron and aluminum increase in the substantia nigra of patients with Parkinson’s disease: an X-ray microanalysis. J Neurochem 56(2):446–451PubMedCrossRefGoogle Scholar
  247. 247.
    Kostka M, Hogen T, Danzer KM, Levin J, Habeck M, Wirth A, Wagner R, Glabe CG, Finger S, Heinzelmann U, Garidel P, Duan W, Ross CA, Kretzschmar H, Giese A (2008) Single particle characterization of iron-induced pore-forming alpha-synuclein oligomers. J Biol Chem 283(16):10992–11003. doi: 10.1074/jbc.M709634200 PubMedCrossRefGoogle Scholar
  248. 248.
    Uversky VN (2007) Neuropathology, biochemistry, and biophysics of alpha-synuclein aggregation. J Neurochem 103(1):17–37. doi: 10.1111/j.1471-4159.2007.04764.x PubMedGoogle Scholar
  249. 249.
    Cole NB, Murphy DD, Lebowitz J, Di Noto L, Levine RL, Nussbaum RL (2005) Metal-catalyzed oxidation of alpha-synuclein: helping to define the relationship between oligomers, protofibrils, and filaments. J Biol Chem 280(10):9678–9690. doi: 10.1074/jbc.M409946200 PubMedCrossRefGoogle Scholar
  250. 250.
    Golts N, Snyder H, Frasier M, Theisler C, Choi P, Wolozin B (2002) Magnesium inhibits spontaneous and iron-induced aggregation of alpha-synuclein. J Biol Chem 277(18):16116–16123. doi: 10.1074/jbc.M107866200 PubMedCrossRefGoogle Scholar
  251. 251.
    Davies P, Moualla D, Brown DR (2011) Alpha-synuclein is a cellular ferrireductase. PLoS One 6(1):e15814. doi: 10.1371/journal.pone.0015814 PubMedPubMedCentralCrossRefGoogle Scholar
  252. 252.
    Brown DR (2013) alpha-Synuclein as a ferrireductase. Biochem Soc Trans 41(6):1513–1517. doi: 10.1042/BST20130130 PubMedCrossRefGoogle Scholar
  253. 253.
    Ortega R, Carmona A, Roudeau S, Perrin L, Ducic T, Carboni E, Bohic S, Cloetens P, Lingor P (2015) alpha-Synuclein Over-Expression Induces Increased Iron Accumulation and Redistribution in Iron-Exposed Neurons. Mol Neurobiol. doi: 10.1007/s12035-015-9146-x
  254. 254.
    Friedlich AL, Tanzi RE, Rogers JT (2007) The 5’-untranslated region of Parkinson’s disease alpha-synuclein messengerRNA contains a predicted iron responsive element. Mol Psychiatry 12(3):222–223. doi: 10.1038/ PubMedCrossRefGoogle Scholar
  255. 255.
    Olivares D, Huang X, Branden L, Greig NH, Rogers JT (2009) Physiological and Pathological Role of Alpha-synuclein in Parkinson’s Disease Through Iron Mediated Oxidative Stress; The Role of a Putative Iron-responsive Element. Int J Mol Sci 10(3):1226–1260. doi: 10.3390/ijms10031226 PubMedPubMedCentralCrossRefGoogle Scholar
  256. 256.
    Zhu ZJ, Wu KC, Yung WH, Qian ZM, Ke Y (2016) Differential interaction between iron and mutant alpha-synuclein causes distinctive Parkinsonian phenotypes in Drosophila. Biochim Biophys Acta 1862(4):518–525. doi: 10.1016/j.bbadis.2016.01.002 PubMedCrossRefGoogle Scholar
  257. 257.
    Curtis AR, Fey C, Morris CM, Bindoff LA, Ince PG, Chinnery PF, Coulthard A, Jackson MJ, Jackson AP, McHale DP, Hay D, Barker WA, Markham AF, Bates D, Curtis A, Burn J (2001) Mutation in the gene encoding ferritin light polypeptide causes dominant adult-onset basal ganglia disease. Nat Genet 28(4):350–354. doi: 10.1038/ng571 PubMedCrossRefGoogle Scholar
  258. 258.
    Harris ZL, Takahashi Y, Miyajima H, Serizawa M, MacGillivray RT, Gitlin JD (1995) Aceruloplasminemia: molecular characterization of this disorder of iron metabolism. Proc Natl Acad Sci U S A 92(7):2539–2543PubMedPubMedCentralCrossRefGoogle Scholar
  259. 259.
    Nichols CG (2006) KATP channels as molecular sensors of cellular metabolism. Nature 440(7083):470–476. doi: 10.1038/nature04711 PubMedCrossRefGoogle Scholar
  260. 260.
    Thomzig A, Pruss H, Veh RW (2003) The Kir6.1-protein, a pore-forming subunit of ATP-sensitive potassium channels, is prominently expressed by giant cholinergic interneurons in the striatum of the rat brain. Brain Res 986(1-2):132–138PubMedCrossRefGoogle Scholar
  261. 261.
    Holemans S, Javoy-Agid F, Agid Y, De Paermentier F, Laterre EC, Maloteaux JM (1994) Sulfonylurea binding sites in normal human brain and in Parkinson’s disease, progressive supranuclear palsy and Huntington’s disease. Brain Res 642(1-2):327–333PubMedCrossRefGoogle Scholar
  262. 262.
    Takanashi M, Mochizuki H, Yokomizo K, Hattori N, Mori H, Yamamura Y, Mizuno Y (2001) Iron accumulation in the substantia nigra of autosomal recessive juvenile parkinsonism (ARJP). Parkinsonism Relat Disord 7(4):311–314PubMedCrossRefGoogle Scholar
  263. 263.
    Altamura S, Muckenthaler MU (2009) Iron toxicity in diseases of aging: Alzheimer’s disease, Parkinson’s disease and atherosclerosis. J Alzheimers Dis 16(4):879–895. doi: 10.3233/JAD-2009-1010 PubMedCrossRefGoogle Scholar
  264. 264.
    Antharam V, Collingwood JF, Bullivant JP, Davidson MR, Chandra S, Mikhaylova A, Finnegan ME, Batich C, Forder JR, Dobson J (2012) High field magnetic resonance microscopy of the human hippocampus in Alzheimer’s disease: quantitative imaging and correlation with iron. Neuroimage 59(2):1249–1260. doi: 10.1016/j.neuroimage.2011.08.019 PubMedCrossRefGoogle Scholar
  265. 265.
    Levenson CW, Cutler RG, Ladenheim B, Cadet JL, Hare J, Mattson MP (2004) Role of dietary iron restriction in a mouse model of Parkinson’s disease. Exp Neurol 190(2):506–514. doi: 10.1016/j.expneurol.2004.08.014 PubMedCrossRefGoogle Scholar
  266. 266.
    Shoham S, Youdim MB (2004) Nutritional iron deprivation attenuates kainate-induced neurotoxicity in rats: implications for involvement of iron in neurodegeneration. Ann N Y Acad Sci 1012:94–114PubMedCrossRefGoogle Scholar
  267. 267.
    Dexter DT, Statton SA, Whitmore C, Freinbichler W, Weinberger P, Tipton KF, Della Corte L, Ward RJ, Crichton RR (2011) Clinically available iron chelators induce neuroprotection in the 6-OHDA model of Parkinson’s disease after peripheral administration. J Neural Transm 118(2):223–231. doi: 10.1007/s00702-010-0531-3 PubMedCrossRefGoogle Scholar
  268. 268.
    Bar-Am O, Amit T, Kupershmidt L, Aluf Y, Mechlovich D, Kabha H, Danovitch L, Zurawski VR, Youdim MB, Weinreb O (2015) Neuroprotective and neurorestorative activities of a novel iron chelator-brain selective monoamine oxidase-A/monoamine oxidase-B inhibitor in animal models of Parkinson’s disease and aging. Neurobiol Aging 36(3):1529–1542. doi: 10.1016/j.neurobiolaging.2014.10.026 PubMedCrossRefGoogle Scholar
  269. 269.
    Kalfon L, Youdim MB, Mandel SA (2007) Green tea polyphenol (-) -epigallocatechin-3-gallate promotes the rapid protein kinase C- and proteasome-mediated degradation of Bad: implications for neuroprotection. J Neurochem 100(4):992–1002. doi: 10.1111/j.1471-4159.2006.04265.x PubMedCrossRefGoogle Scholar
  270. 270.
    Wang J, Du XX, Jiang H, Xie JX (2009) Curcumin attenuates 6-hydroxydopamine-induced cytotoxicity by anti-oxidation and nuclear factor-kappa B modulation in MES23.5 cells. Biochem Pharmacol 78(2):178–183. doi: 10.1016/j.bcp.2009.03.031 PubMedCrossRefGoogle Scholar
  271. 271.
    Wang YQ, Wang MY, Fu XR, Peng Y, Gao GF, Fan YM, Duan XL, Zhao BL, Chang YZ, Shi ZH (2015) Neuroprotective effects of ginkgetin against neuroinjury in Parkinson’s disease model induced by MPTP via chelating iron. Free Radic Res:1-12. doi: 10.3109/10715762.2015.1032958
  272. 272.
    Beard JL, Erikson KM, Jones BC (2002) Neurobehavioral analysis of developmental iron deficiency in rats. Behav Brain Res 134(1-2):517–524PubMedCrossRefGoogle Scholar
  273. 273.
    Erikson KM, Jones BC, Beard JL (2000) Iron deficiency alters dopamine transporter functioning in rat striatum. J Nutr 130(11):2831–2837PubMedGoogle Scholar
  274. 274.
    Youdim MB (2008) Brain iron deficiency and excess; cognitive impairment and neurodegeneration with involvement of striatum and hippocampus. Neurotox Res 14(1):45–56PubMedCrossRefGoogle Scholar
  275. 275.
    Beard J, Erikson KM, Jones BC (2003) Neonatal iron deficiency results in irreversible changes in dopamine function in rats. J Nutr 133(4):1174–1179PubMedGoogle Scholar
  276. 276.
    Unger EL, Paul T, Murray-Kolb LE, Felt B, Jones BC, Beard JL (2007) Early iron deficiency alters sensorimotor development and brain monoamines in rats. J Nutr 137(1):118–124PubMedGoogle Scholar
  277. 277.
    Doraiswamy PM, Finefrock AE (2004) Metals in our minds: therapeutic implications for neurodegenerative disorders. Lancet Neurol 3(7):431–434. doi: 10.1016/S1474-4422(04)00809-9 PubMedCrossRefGoogle Scholar
  278. 278.
    Song N, Wang J, Jiang H, Xie J (2010) Ferroportin 1 but not hephaestin contributes to iron accumulation in a cell model of Parkinson’s disease. Free Radic Biol Med 48(2):332–341. doi: 10.1016/j.freeradbiomed.2009.11.004 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, Shandong Provincial Collaborative Innovation Center for Neurodegenerative DisordersMedical College of Qingdao UniversityQingdaoChina
  2. 2.Neurochemistry Laboratory, Division of Psychiatric Neurosciences and Genetics and Aging Research UnitMassachusetts General HospitalBostonUSA

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